Spinal cord synaptic plasticity is increasingly recognized as important in pain and analgesia. Synaptic plasticity may also be important in drug-induced tolerance and withdrawal. In the past funding period we have obtained evidence that the spinal potency of both opioid analgesics and ethanol is negatively modulated by the development of acute neuronal tolerance, and that withdrawal hyperresponsiveness is associated with these agents. In addition we have partially characterized a form of stimulus-induced long-term potentiation (LTP) in spinal cord that may serve as a model for the central sensitization associated with pathologic pain states. Although the cellular loci and detailed mechanisms for these forms of spinal plasticity almost certainly differ, there may be a broadly common mechanism of receptor phosphorylation mediated by protein kinase C. We will test the overall hypothesis that opioids, ethanol, volatile general anesthetic agents and high frequency nociceptive afferent stimulation induce spinal hyperexcitability by altering the phosphorylation state of one or more critical receptor/ion channel complexes in spinal cord neurons, with particular attention to calcium-permeable ion channels. There are four Specific Aims, each linked to mechanistic hypotheses. 1. Clinical inhalation anesthetic agents, like ethanol, induce rapid acute neuronal tolerance and withdrawal in spinal cord motor neurons. Tolerance and/or withdrawal to ethanol and volatile anesthetics are mediated by protein kinase C and depend on increased calcium influx. 2. Mu opiod analgesics induce rapid acute tolerance as well as withdrawal in spinal cord by an action involving protein kinase C leading to increased calcium influx via NMDA receptors. 3. Spinal LTP shares a common mechanism with acute opioid tolerance and withdrawal. 4. Synergistic actions between several classes of agents are due to block of rapid acute tolerance. All experiments will be carried out in vitro in spinal cords from young rats, using population ventral root responses evoked by dorsal root stimulation in whole cords and patch recording from visually identified motor neurons in spinal cord slices. The results will shed light on the mechanistic basis for anesthetic and analgesic drug potency. Clinically tolerance to opioid analgesics is a major problem in the treatment of chronic pain. Rapid acute tolerance is becoming recognized as a major determinant of sensitivity to ethanol. Tolerance and withdrawal are not yet accepted for most inhalation anesthetic agents, and if demonstrated will cause a change in the way the clinical and theoretical properties of these agents are considered.